In an aging population, neurodegeneration associated with Parkinson's disease, Alzheimer's disease, Lewy Body Dementia, and Huntington's disease is a growing health burden.
Among these neurodegenerative disorders, the pathophysiology of Parkinson's disease (PD) has been particularly well studied.
Mechanistically, the motor symptoms of PD are linked to death of dopamine-producing neurons in the midbrain's substantia nigra and to the deposition of Lewy bodies in various brain regions. Desensitization of the dopamine response system has also been documented, suggesting that both production and efficacy of dopamine are compromised in the disease. Most of the existing agents currently approved for treating PD address symptoms of dopamine depletion, such as bradykinesia, and do not modify disease progression.
Mitochondrial function is central to PD pathogenesis. In the 1980s, users of the illicit drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a mitochondrial electron transport chain complex I inhibitor, developed PD. Their symptoms and eventual autopsy findings recapitulated aspects of PD. While Lewy bodies were noticeably absent (also a finding in MPTP-treated primates), dopamine therapy was transiently successful, indicating that the other arm of the PD pathology was a feature of MPTP exposure. Since these studies, a wealth of literature has affirmed the linkage between mitochondria, specifically oxidation, and PD. In addition, mitochondrial Complex I and III have been implicated, and the linkage between their production of reactive oxygen species and oxidative stress in the PD brain/dopaminergic neurons has been elucidated.
Cannabinoids have been suggested as potential agents for treating a spectrum of neurological disorders, including PD.
A priori, cannabinoids would appear to be promising drugs for targeting the mechanistic pathways that underlie PD, and potentially modifying disease progression. First, they are clearly capable of acting as anti-oxidants, specifically opposing oxidative stress at the mitochondrion. Second, cannabinoid receptors are located in the brain regions compromised in PD, with the globus pallidus and substantia nigra pars reticulate showing some of the highest CB1 receptor expression levels in the brain, and also expressing the ionotropic cannabinoid receptor TRPV1. Third, cannabinoids are pro-survival factors in neurons, and protect against oxidatively-induced cell death. There is even evidence that isolated cannabinoid compounds can act as anti-aggresomal factors, with delta-9 tetra-hydrocannabinol (THC) binding directly to Aß plaque peptides in Alzheimer's disease and causing disaggregation. Cannabinoids are pro-clearance, encouraging autophagy and dissolution of inclusion bodies.
Taken together, these functions of the endo-cannabinoid system position their exogenous counterparts extremely well as theoretical intervention strategies in pathological brain aging. Indeed, CB1-deficient mice display early onset of cognitive decline and the histological and molecular features that are common to PD, and smoked and ingested marijuana has been associated with both transient and sustained improvement in motor function, decreased pain and improved motor function in anecdotal reports of patient experiences.
Although a number of cannabinoids have been tested individually or in pairs, the tested cannabinoid compositions have not demonstrated the predicted therapeutic effects, and in particular, have not proven comparable in efficacy to the use of the whole Cannabis plants. This may be due to the complexity of compounds present in each Cannabis plant, coupled with the huge variability existing in various Cannabis strains. It is also possible that minor components of Cannabis plants (cannabinoids and other naturally occurring components) contribute positively or negatively to the overall therapeutic effects.
A number of research studies suggest that effective therapeutics for PD should target not only restoration of dopamine production, but also address calcium-overload induced cell death. See, e.g., Cali et al., Cell Tissue Res. 357(2):439-54 (2014); Kang et al., Nature Communications 3, Article number: 1146 (2012). Cannabis mixtures that contain ligands for cation channels (such as TRPV1) may be of limited therapeutic potential if these calcium-overload inducing components are not identified and removed.
Thus, there is a continuing need for novel and validated pharmacological agents for the treatment of PD and other neurodegenerative diseases. There is a particular need for well-defined compositions of cannabinoids that are effective for the treatment of PD and other neurodegenerative diseases.